Abstract: Aging is the greatest risk factor for the development of the debilitating neurodegenerative disorder Alzheimer's disease (AD). Histopathologically, AD is characterized by the accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles (consisting of hyperphosphorylated and aggregated tau) in the brain, which are accompanied by dramatic synaptic and neuronal loss. Deposition of abnormally phosphorylated tau is also common in the normal aging brain. Despite evidence that pathologic tau accumulation and synaptic alterations correlate with cognitive deficits in AD patients, the mechanism(s) underlying such alterations remain incompletely characterized. Growing evidence points to disturbances in mitochondrial and synaptic function; processes also affected by normal aging. Our preliminary data suggest that pathologic tau accumulates within nerve terminals and associates with presynaptic mitochondria from hTau mice in an age-dependent manner, resulting in development of an aged metabolic phenotype, namely alterations of presynaptic mitochondrial parameters and impairment of spare respiratory capacity in nerve terminals, suggesting neuronal synapses may be particularly vulnerable to both aging- and pathologic tau- induced mitochondrial dysfunction. Specific Aim 1 will determine how pathologic tau accumulation contributes to presynaptic mitochondrial functional and proteomic alterations, and Specific Aim 2 will examine how pathologic tau accumulation contributes to presynaptic mitochondrial DNA damage, associated with normal aging. Specific Aim 3 will assess Parkin function as a target to ameliorate the presynaptic mitochondrial dysfunction associated with pathologic tau accumulation. Innovative aspects include our mechanistic studies to identify possible new targets for AD based on overlapping changes that we observe with normal brain aging and in the context of tau pathology, specifically, alterations in presynaptic mitochondrial function. These R01 studies will help bridge this gap in our knowledge and lead to future studies to identify strategies to alleviate such mechanisms(s) of disease pathogenesis.